Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) available in the market for the treatment of major depressive disorder. It is chemically (+)-(S)—N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride as represented by Formula I:

The processes for the preparation of duloxetine hydrochloride are provided in several prior art references.
U.S. Pat. No. 5,362,886 provides a process for preparing duloxetine hydrochloride, wherein an ethyl acetate solution of duloxetine free base is treated with concentrated hydrochloride acid, followed by further addition of ethyl acetate. The solid so obtained is isolated from the reaction mixture by concentration and subsequent filtration. The solid is then washed with chilled ethyl acetate to obtain duloxetine hydrochloride.
Wheeler, W. J., et al J. Label. Cpds. Radiopharm., 1995, 36, 312 provides a process for preparing duloxetine hydrochloride, wherein an ethyl acetate solution of duloxetine free base is treated with hydrochloric acid in ethyl acetate. The solid so obtained is isolated from the reaction mixture by the addition of ether and subsequent filtration. The solid is then washed with fresh ether and dried to obtain duloxetine hydrochloride. Similar process for preparing duloxetine hydrochloride is also provided in PCT Publication No. WO 2007/077580, wherein the final solid product is washed with ethyl acetate and dried to obtain duloxetine hydrochloride. Our co-pending Indian Patent Application No. 1554/DEL/2006 provides a process for preparing duloxetine hydrochloride, wherein an ethyl acetate solution of duloxetine free base is treated with hydrochloric acid in ethyl acetate to obtain duloxetine hydrochloride, which is further purified by recrystallization from ethanol and diisopropyl ether.
PCT Publication No. WO 2007/076733 provides a process for preparing duloxetine hydrochloride, wherein an ethylmethylketone solution of duloxetine free base is treated with concentrated hydrochloride acid. The duloxetine hydrochloride so obtained is isolated from the reaction mixture by concentration under vacuum. Similar process for preparing duloxetine hydrochloride is also provided in PCT Publication No. WO 2007/038253.
U.S. Patent Application Publication No. 2006/0194869 provides a process for preparing duloxetine hydrochloride, wherein an acetone solution of duloxetine free base is bubbled with hydrogen chloride gas. The solid so obtained is isolated from the reaction mixture by filtration. The solid is washed with acetone and dried in vacuum to obtain duloxetine hydrochloride.
According to prior art methods, duloxetine free base is treated with hydrochloric acid in the presence of ester or ketone solvents. The prior art methods employ hydrochloric acid in concentrated form, in diluted forms with ethyl acetate, or as a gas. The solid obtained is isolated by concentration and/or filtration, which is subsequently washed and dried to obtain duloxetine hydrochloride. Washing is generally carried out to remove the soluble by-products and drying is finally carried out to remove the residual solvents. The present inventors have observed that even after usual washing and drying steps, the finally obtained duloxetine hydrochloride is contaminated with 4-[3-(methylamino)-1-thiophen-2-ylpropyl]naphthalen-1-ol of Formula II in undesirable amounts.

PCT Publication Nos. WO 2007/105021, WO 2007/119116 and WO 2007/134168 provide methods for preparing and detecting 4-[3-(methylamino)-1-thiophen-2-ylpropyl]naphthalen-1-ol of Formula II in duloxetine hydrochloride. The present inventors have observed that the formation of this compound essentially takes place during the drying process. The present inventors have further observed that the compound of Formula II is formed more than about 80% during drying even if washing is carried out two or three times. Further, the formation of this impurity is observed to be a critical problem when duloxetine hydrochloride is prepared in large scale.